FDA Approval Sought for Imetelstat for Transfusion-Dependent Anemia in Select MDS

A new drug application (NDA) seeking the approval of imetelstat for use as a therapeutic option for transfusion-dependent anemia in adult patients with low- to intermediate-1 risk myelodysplastic syndrome (MDS) who have not responded to, lost response to, or were not candidates for erythropoiesis-stimulating agents (ESAs) has been submitted to the FDA.¹

The NDA is supported by findings from the phase 3 IMerge trial (NCT02598661), in which treatment with imetelstat (n = 118) resulted in a higher 8-week red blood cell transfusion independence (RBC-TI) rate than placebo (n = 59) in this population, at 39.8% (95% CI, 30.9%-49.3%) and 15.0% (95% CI, 7.1%-26.6%), respectively (P < .001), meeting the primary end point of the trial.²

Additionally, patients who received imetelstat experienced a higher 16-week RBC-TI rate than those given placebo, at 31.4% (95% CI, 23.1%-40.5%) and 6.7% (95% CI, 1.9%-16.2%), respectively (P < .001); this was also true with regard to the 24-week RBI-TI rate, at 28.0% (95% CI, 20.1%-37.0%) and 3.3% (95% CI, 0.4%-11.5%), respectively (P < .001). The TI rate at 1 year in the investigative arm was 13.6% (95% CI, 8.0%-21.1%) vs 1.7% (95% CI, 0.0%-8.9%) in the control arm (P = .012).

“The pioneering achievement to submit the first NDA to the FDA for a telomerase inhibitor reflects the dedication, commitment, and teamwork of so many people who believed targeting telomerase could make a significant difference for patients,” John A. Scarlett, MD, chairman and chief executive officer at Geron Corporation, stated in a press release.¹ “We are deeply committed to addressing the unmet needs for [patients with] lower-risk myelodysplastic syndrome [MDS] who often suffer from transfusion-dependent anemia.”

Imetelstat utilizes a novel approach in which oligonucleotides inhibit the activity of telomerase.3 The agent binds to the enzyme and selectively eliminates malignant stem and progenitor cells in the bone marrow and allows for non-malignant bone marrow and blood cell production to recover. In prior phase 2 trials, the agent has been shown to have disease-modifying activity in those with lower-risk MDS and myelofibrosis.

The double-blind, placebo-controlled, randomized trial enrolled patients with low- or intermediate-1 risk MDS by International Prognostic Scoring System (IPSS) criteria. Patients must have been relapsed or refractory to an ESA. If ineligible for an ESA, patients were required to be relapsed or refractory to an erythropoietin administered at a dose above 500 mU/mL. Other inclusion criteria included transfusion dependence. They could not have previously received lenalidomide (Revlimid) or a hypomethylating agent.

Study participants were randomly assigned 2:1 to receive imetelstat at 7.5 mg/kg intravenously or placebo every 4 weeks. Stratification factors included transfusion burden (4 to 6 units vs > 6 units) and IPSS risk category (low vs intermediate-1).

In addition to RBC-TI at 8 weeks serving as the primary end point of the research, 24-week RBC-TI, TI duration, hematologic improvement-erythroid, and safety represented important secondary end points. Changes in variant allele frequency and patient-reported outcomes were also assessed.

Patient characteristics at baseline were reportedly well balanced between the treatment arms. Across the arms, the median age was 72.5 years (range, 39-87) and most patients were men (63.5%), had IPSS low-risk disease (66.5%), and previously received an ESA (89.5%). Notably, more than half of patients (62%) had ring sideroblasts per World Health Organization classification. Moreover, 54% of patients had at least 4, but no more than 6, units of RBC transfusions per 8 weeks.

The median time to diagnosis was slightly longer in the imetelstat arm vs the placebo arm, at 3.5 years (range, 0.1-26.7) vs 2.8 years (range, 0.2-25.7), and median hemoglobin levels prior to treatment were 7.9 g/dL (range, 5.3-10.1) and 7.8 g/dL (range, 6.1-9.2), respectively. Additionally, the median prior RBC transfusion burden was 6 units per 8 weeks in both arms (range, 4-33).

Additional data presented at the 2023 ASCO Annual Meeting showed that 8-week RBC-TI rates favored the telomerase inhibitor over placebo spanning many key lower-risk MDS subsets including those without ring sideroblasts (P = .038), those who previously had over 6 unites of RBC transfusions per 8 weeks (P = .023), and those with IPSS intermediate-1 risk disease (P = .004).

Those who received imetelstat also experienced a significant increase in hemoglobin levels. Those who had TI independence at 8 weeks experienced a median rise of 3.6 g/dL (range, -0.1 to 13.8) compared with 0.8 g/dL (range, -0.2 to 1.7) with placebo. The median peak hemoglobin levels in the investigative and control arms were 11.3 g/dL (range, 8.0-21.9) and 8.9 g/dL (range, 7.9-9.7), respectively.

Additionally, those who received imetelstat also experienced a higher rate of hematologic improvement-erythroid vs those given placebo, at 42.4% (95% CI, 33.3%-51.8%) and 13.3% (95% CI, 5.9%-24.6%), respectively (P < .001). In those with low transfusion burden, 16-week TI rates were 33.3% (95% CI, 14.6%-57.0%) in those given imetelstat (n = 21) and 22.2% (95% CI, 6.4%-47.6%) in those given placebo (n = 18; P = .562). In those with a high transfusion burden, these rates with imetelstat (n = 97) and placebo (n = 42) were 30.0% (95% CI, 21.9%-41.1%) and 0% (95% CI, 0.0%-8.4%), respectively.

Regarding safety, patients who received imetelstat experienced any-grade toxicities that included thrombocytopenia (75%), neutropenia (74%), anemia (20%), COVID-19 (19%), and asthenia (19%); these effects were grade 3 or 4 in 62%, 68%, 19%, 2%, and 0% of patients, respectively.

The median duration of thrombocytopenia was 1.4 weeks (range, 0.1-12.6) in the imetelstat arm and 2.0 weeks (range, 0.3-11.6) in the placebo arm; 86.3% and 44.4% of cases, respectively, resolved within 4 weeks. The median duration of neutropenia in the investigative and control arms was 1.9 weeks (range, 0.0-15.9) and 2.2 weeks (range, 1.0-4.6), respectively, with 81.0% and 50.0% of cases resolving within 4 weeks.

In the investigative and control arms, grade 3 or 4 bleeding events were reported in 2.5% and 1.7% of patients, respectively, infections occurred in 11.0% and 13.6% of patients, respectively, and febrile neutropenia was observed in 0.8% and 0% of patients, respectively.

About 75% of patients who received imetelstat required dose modifications because of toxicities and less than 15% of patients discontinued treatment. The most common reason for discontinuation in the imetelstat and placebo arms, respectively, was lack of efficacy (23.7% vs 42.4%, respectively), followed by other (16.1% vs 20.3%), adverse effects (16.1% vs 0%), disease relapse after response (14.4% vs 1.7%), progressive disease (5.9% vs 8.5%), and death (0.8% vs 3.4%).

Geron Corporation shared that they have requested that the FDA grant priority review of the application and they expect communication from the agency within 60 days to know whether the NDA has been accepted for review, as is standard practice.¹ They also shared plans to submit a marketing authorization application to the European Union in the second half of 2023.

References:

1. Geron announces submission of new drug application to FDA for first-in-class telomerase inhibitor imetelstat. News release. Geron Corporation. June 20, 2023. Accessed June 21, 2023. https://ir.geron.com/investors/press-releases/press-release-details/2023/Geron-Announces-Submission-of-New-Drug-Application-to-FDA-for-First-in-Class-Telomerase-Inhibitor-Imetelstat/default.aspx
2. Zeidan AM, Platzbecker U, Santini V, et al. IMerge: Results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (TD) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). J Clin Oncol. 2023;41(suppl 16):7004. doi:10.1200/JCO.2023.41.16_suppl.7004
3. A first-in-class investigational drug with the potential to extend and enhance lives. Geron Corporation website. Accessed June 21, 2023. https://www.geron.com/research-and-development/imetelstat/